In the dose titration of a patient, the objective is to attain and maintain a blood level of drug substance that exceeds the minimum effective level required for response but does not exceed the minimum toxic level. Absorption of a drug from an oral dosage form such as a tablet or a capsule can be affected by properties of the formulation and its method of manufacture. This is particularly true when the drug has low solubility in water, has a hydrophobic nature, and/or is administered in high therapeutic doses. In such cases, dissolution of the drug from the dosage form in the gastrointestinal tract can be the limiting factor that determines the rate and extent of absorption of drug into the body. Changes in the composition and/or method of manufacture of the dosage form can affect the dissolution rate.
An active area of research is in the discovery of new methods of drug formulation. Drug release from a solid dosage form can be enhanced by addition of materials referred to as disintegrants. Disintegrants are substances or a mixture of substances added to the drug formulation that facilitate the breakup or disintegration of the tablet or capsule contents into smaller particles that dissolve more rapidly than in the absence of the disintegrant (Handbook of Pharmaceutical Excipients, Ainley Wade and Paul J. Weller eds., 2d ed. 1994; The Theory and Practice of Industrial Pharmacy, Leon Lachman, Herbert A. Lieberman, and Joseph L. Kanig eds., 3rd ed. 1986; Disintegrating Agents in Hard Gelatin Capsules, John E. Botzolakis and Larry L. Augsburger, Drug Development and Industrial Pharmacy 14(1), 29-41 1988). Materials that serve as disintegrants include starches, clays, celluloses, algins, gums and cross-linked polymers. A group of disintegrants referred to as "super-disintegrants" are generally used at a low level in the solid dosage form, typically 1 to 10% by weight relative to the total weight of the dosage unit. Examples of super-disintegrants are croscarmelose, crospovidone and sodium starch glycolate, which represent examples of a cross-linked cellulose, a cross-linked polymer and a cross-linked starch, respectively. EP 0,301,006 describes the use of super-disintegrants to enhance the dissolution properties of tablet and capsule formulations containing methylprednisolone, a glucocorticoid steroid.
It is desirable to develop formulations where the tablet or capsule disintegrates rapidly and the pharmaceutical agent dissolves readily. This is especially important where the pharmaceutical agent is highly insoluble and/or must be administered in high-strength dosage forms.
This invention relates to new solid oral dosage form formulations containing the HIV drug efavirenz that enhance the dissolution rate of efavirenz in the gastrointestinal tract in order to improve the rate and extent of absorption into the body, thereby improving its therapeutic effect.